scholarly journals SHP2 as a Potential Therapeutic Target in Diffuse-Type Gastric Carcinoma Addicted to Receptor Tyrosine Kinase Signaling

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4309
Author(s):  
Yuko Nagamura ◽  
Makoto Miyazaki ◽  
Yoshiko Nagano ◽  
Arata Tomiyama ◽  
Rieko Ohki ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Tyrosine Phosphorylation ◽  
Cell Lines ◽  
Gene Amplification ◽  
Therapeutic Target ◽  
Peritoneal Dissemination ◽  
Migration And Invasion ◽  
Diffuse Type ◽  
Pharmacological Inhibition ◽  
Mouse Xenograft Model

Diffuse-type gastric carcinoma (DGC) exhibits aggressive progression associated with rapid infiltrative growth, massive fibrosis, and peritoneal dissemination. Gene amplification of Met and fibroblast growth factor receptor 2 (FGFR2) receptor tyrosine kinases (RTKs) has been observed in DGC. However, the signaling pathways that promote DGC progression downstream of these RTKs remain to be fully elucidated. We previously identified an oncogenic tyrosine phosphatase, SHP2, using phospho-proteomic analysis of DGC cells with Met gene amplification. In this study, we characterized SHP2 in the progression of DGC and assessed the therapeutic potential of targeting SHP2. Although SHP2 was expressed in all gastric carcinoma cell lines examined, its tyrosine phosphorylation preferentially occurred in several DGC cell lines with Met or FGFR2 gene amplification. Met or FGFR inhibitor treatment or knockdown markedly reduced SHP2 tyrosine phosphorylation. Knockdown or pharmacological inhibition of SHP2 selectively suppressed the growth of DGC cells addicted to Met or FGFR2, even when they acquired resistance to Met inhibitors. Moreover, SHP2 knockdown or pharmacological inhibition blocked the migration and invasion of Met-addicted DGC cells in vitro and their peritoneal dissemination in a mouse xenograft model. These results indicate that SHP2 is a critical regulator of the malignant progression of RTK-addicted DGC and may be a therapeutic target.

scholarly journals PLEKHA5 regulates the survival and peritoneal dissemination of diffuse-type gastric carcinoma cells with Met gene amplification

Oncogenesis ◽  
2021 ◽  
Vol 10 (3) ◽  
Author(s):  
Yuko Nagamura ◽  
Makoto Miyazaki ◽  
Yoshiko Nagano ◽  
Masako Yuki ◽  
Kiyoko Fukami ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Gene Amplification ◽  
Peritoneal Dissemination ◽  
Acquired Resistance ◽  
Pleckstrin Homology Domain ◽  
Diffuse Type ◽  
Jnk Pathway ◽  
Downstream Effector ◽  
Promising Therapeutic Target

AbstractMet gene amplification has been found in a subset of malignant carcinomas, including diffuse-type gastric carcinoma (DGC), which has a poor prognosis owing to rapid infiltrative invasion and frequent peritoneal dissemination. Met is considered a promising therapeutic target for DGC. However, DGC cells with Met gene amplification eventually acquire resistance to Met inhibitors. Therefore, identification of alternate targets that mediate Met signaling and confer malignant phenotypes is critical. In this study, we conducted a phosphoproteomic analysis of DGC cells possessing Met gene amplification and identified Pleckstrin Homology Domain Containing A5 (PLEKHA5) as a protein that is tyrosine-phosphorylated downstream of Met. Knockdown of PLEKHA5 selectively suppressed the growth of DGC cells with Met gene amplification by inducing apoptosis, even though they had acquired resistance to Met inhibitors. Moreover, PLEKHA5 silencing abrogated the malignant phenotypes of Met-addicted DGC cells, including peritoneal dissemination in vivo. Mechanistically, PLEKHA5 knockdown dysregulates glycolytic metabolism, leading to activation of the JNK pathway that promotes apoptosis. These results indicate that PLEKHA5 is a novel downstream effector of amplified Met and is required for the malignant progression of Met-addicted DGC.

scholarly journals LncRNA AC008972.1 as a Novel Therapeutic Target for Prostate Cancer

2021 ◽  
Author(s):  
Jia Liu ◽  
Qijin Wu ◽  
Ruiyu Song ◽  
Wen Miao ◽  
Yuting Ma ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Protein Expression ◽  
Cell Viability ◽  
Therapeutic Target ◽  
Xenograft Model ◽  
Migration And Invasion ◽  
Down Regulation ◽  
Mouse Xenograft Model ◽  
Novel Therapeutic

Abstract Background: Prostate cancer is the leading cause of disease and death in men. Long non-coding RNAs (lncRNAs), microRNA (miRNAs) and mRNAs networks mediate prostate cancer progression. Here, we aim to investigate functions of lncRNA AC008972.1/miR-143-3p/thousand-and-one-amino acid 2 kinase (TAOK2) in prostate cancer. Methods: The expression levels of lncRNA AC008972.1, miR-143-3p and TAOK2 are detected in prostate cancer tissues and cell lines by RT-qPCR. PC3 and LNCaP cells are used to establish lncRNA AC008972.1-knockdown, miR-143-3p-overexpressing, and TAOK2-down-regulated cells. Cell viability is examined by MTT and cell proliferation is detected by clone formation assay. Cell migration and invasion are tested by wound scratch assay and transwell chamber assay. The rate of apoptosis was analyzed by flow cytometry. The protein expression is detected by western blot assay. The target is validated by RNA binding protein immunoprecipitation (RIP) assay and dual luciferase activity assay. A mouse xenograft model was conducted to investigate the oncogenic effect of lncRNA AC008972.1 on prostate cancer. Results: High expression of lncRNA AC008972.1 was associated with low overall survival in prostate cancer. Down-regulation of lncRNA AC008972.1 delayed prostate cancer process by inhibiting cell viability, proliferation, migration and invasion, as well as altering protein expression，whereas cell apoptosis was markedly promoted. LncRNA AC008972.1 negatively regulated miR-143-3p expression and miR-143-3p overexpression promoted prostate cancer process in vitro. TAOK2 expression was decreased by miR-143-3p through the complementary targeting of TAOK2 mRNA. Down-regulation of lncRNA AC008972.1 mitigated prostate cancer process in vitro based on miR-143-3p/TAOK2 node. Furthmore, the data of xenograft model experiment showed that inhibition of lncRNA AC008972.1 suppressed tumor growth in vivo. Conclusions: Collectively, knockdown of lncRNA AC008972.1 inhibits prostate cancer cell growth based on down-regulation of TAOK2 induced by miR-143-3p. Here, we identify that lncRNA AC008972.1 exerts essential roles in the progression of prostate cancer and serves as a novel therapeutic target for prostate cancer.

scholarly journals tRNA-Derived Fragment tRF-Glu-TTC-027 Regulates the Progression of Gastric Carcinoma via MAPK Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Weiguo Xu ◽  
Bin Zhou ◽  
Juan Wang ◽  
Li Tang ◽  
Qing Hu ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Migration And Invasion ◽  
Underlying Mechanisms

Transfer RNA-derived RNA fragments (tRFs) belong to non-coding RNAs (ncRNAs) discovered in most carcinomas. Although some articles have demonstrated the characteristics of tRFs in gastric carcinoma (GC), the underlying mechanisms still need to be elucidated. Meanwhile, it was reported that the MAPK pathway was momentous in GC progression. Thus we focused on investigating whether tRF-Glu-TTC-027 could act as a key role in the progression of GC with the regulation of the MAPK pathway. We collected the data of the tRNA-derived fragments expression profile from six paired clinical GC tissues and corresponding adjacent normal samples in this study. Then we screened tRF-Glu-TTC-027 for analysis by using RT-PCR. We transfected GC cell lines with tRF-Glu-TTC-027 mimics or mimics control. Then the proliferation, migration, and invasion assays were performed to assess the influence of tRF-Glu-TTC-027 on GC cell lines. Fluorescence in situ hybridization assay was conducted to confirm the cell distribution of tRF-Glu-TTC-027. We confirmed the mechanism that tRF-Glu-TTC-027 influenced the MAPK signaling pathway and observed a strong downregulation of tRF-Glu-TTC-027 in clinical GC samples. Overexpression of tRF-Glu-TTC-027 suppressed the malignant activities of GC in vitro and in vivo. MAPK signaling pathway was confirmed to be a target pathway of tRF-Glu-TTC-027 in GC by western blot. This is the first study to show that tRF-Glu-TTC-027 was a new tumor-suppressor and could be a potential object for molecular targeted therapy in GC.

Integrin α5 mediates cancer cell-fibroblast adhesion and peritoneal dissemination of diffuse-type gastric carcinoma

2021 ◽  
Author(s):  
Shingo Miyamoto ◽  
Yoshiko Nagano ◽  
Makoto Miyazaki ◽  
Yuko Nagamura ◽  
Kazuki Sasaki ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Cancer Cell ◽  
Peritoneal Dissemination ◽  
Diffuse Type ◽  
Integrin Α5 ◽  
Fibroblast Adhesion

scholarly journals KIF3C Promotes Proliferation, Migration, and Invasion of Glioma Cells by Activating the PI3K/AKT Pathway and Inducing EMT

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Yang Gao ◽  
Hui Zheng ◽  
Liangdong Li ◽  
Changshuai Zhou ◽  
Xin Chen ◽  
...  
Keyword(s):  
Cell Lines ◽  
Therapeutic Target ◽  
Glioma Cell ◽  
Glioma Cells ◽  
Motor Protein ◽  
Akt Pathway ◽  
Migration And Invasion ◽  
Exact Function ◽  
Glioma Cell Lines ◽  
Kinesin Superfamily

Kinesin superfamily protein 3C (KIF3C), a motor protein of the kinesin superfamily, is expressed in the central nervous system (CNS). Recently, several studies have suggested that KIF3C may act as a potential therapeutic target in solid tumors. However, the exact function and possible mechanism of the motor protein KIF3C in glioma remain unclear. In this study, a variety of tests including CCK-8, migration, invasion, and flow cytometry assays, and western blot were conducted to explore the role of KIF3C in glioma cell lines (U87 and U251). We found that overexpression of KIF3C in glioma cell lines promoted cell proliferation, migration, and invasion and suppressed apoptosis, while silencing of KIF3C reversed these effects. Ectopic KIF3C also increased the expression of N-cadherin, vimentin, snail, and slug to promote the epithelial-mesenchymal transition (EMT). Mechanistically, overexpression of KIF3C increased the levels of phosphatidylinositol 3-kinase (PI3K) and phosphorylated protein kinase B (p-AKT). These responses were reversed by KIF3C downregulation or AKT inhibition. Our results indicate that KIF3C promotes proliferation, migration, and invasion and inhibits apoptosis in glioma cells, possibly by activating the PI3K/AKT pathway in vitro. KIF3C might act as a potential biomarker or therapeutic target for further basic research or clinical management of glioma.

scholarly journals FBXW7 circular RNA regulates proliferation, migration and invasion of colorectal carcinoma through NEK2, mTOR, and PTEN signaling pathways in vitro and in vivo

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Haoran Lu ◽  
Baofu Yao ◽  
Xinyuan Wen ◽  
Baoqing Jia
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Cell Migration ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Therapeutic Target ◽  
Circular Rna ◽  
Migration And Invasion ◽  
Potential Therapeutic Target

Abstract Backgrounds A number of circular RNAs (circRNAs) have been identified in various cancer including F-box and WD repeat domain containing 7 (FBXW7) circular RNA (circ-FBXW7), which can suppress glioma cell growth. However, the role of circ-FBXW7 in colorectal cancer (CRC) remains unclear. We aimed to investigate the effect and mechanisms of circ-FBXW7 on CRC progression. Methods The expression of circ-FBXW7 in CRC patients was detected by PCR. Stably knockdown of circ-FBXW7 (si circ-FBXW7) cell lines and overexpression of circ-FBXW7 (oe circ-FBXW7) cell lines were constructed by small interfering RNA method and plasmids transfection in CRC SW480 and SW620 cells. The functional experiments including cell proliferation, migration and invasion were carried out by cell counting kit-8 (CCK-8) assay, wound healing assay and trans well assay. The xenograft animal models were established to evaluate the effect and the underlying molecular mechanisms of circ-FBXW7 on CRC progression. Results CRC samples had a significantly lower level of circ-FBXW7 compared to normal tissue. si circ-FBXW7 notably promoted the proliferation, colony formation, cell migration and invasion of CRC cell in vitro. On contrast, circ-FBXW7 overexpressed significantly suppressed CRC cell proliferation, migration and invasion. Similarly, si circ-FBXW7 stimulated the tumor growth and circ-FBXW7 overexpression repressed the tumor progression in SW480 and SW620 tumor models, which suggested that circ-FBXW7 could serve as a target biomarker of CRC. Further study found that si circ-FBXW7 up-regulated the mRNA and protein expressions of NEK2 and mTOR, and diminished the PTEN expression. Whereas, overexpressed circ-FBXW7 induced the tumor suppression via reversing the expressions of NEK2, mTOR, and PTEN. Conclusion circ-FBXW7 plays a major role in controlling the progression of CRC through NEK2, mTOR, and PTEN signaling pathways and may be a potential therapeutic target for CRC treatment. Graphical abstract Circ-FBXW7 controls the progression of CRC through NEK2, mTOR, and PTEN signaling pathways and its overexpression inhibits colorectal cancer cell migration and invasion, suggesting the potential therapeutic target for CRC treatment.

scholarly journals LncRNA SNHG22 Sponges miR-128-3p to Promote Progression of Colorectal Cancer through Upregulating E2F3

2020 ◽  
Author(s):  
Yao Jianning ◽  
Wang Chunfeng ◽  
Dong Xuyang ◽  
Zhang Yanzhen ◽  
Li Yanle ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Expression Levels ◽  
Qrt Pcr ◽  
Mouse Xenograft Model ◽  
Mechanistic Investigation

Abstract Background: Long non-coding RNA (lncRNA) termed small nucleolar RNA host gene 22 (SNHG22) has been reported as a crucial regulator in several types of human cancers. In this study, we aimed to evaluate the function and mechanism of SNHG22 in colorectal cancer (CRC) progression. Methods: Quantitative RT-PCR (qRT-PCR) was used to detect the expression of SNHG22 in adenoma, tumor tissues (TTs), and adjacent nontumorous tissues (ANTs). The biological behaviors of SNHG22 in CRC cell lines were explored both in vitro (CCK-8 assay, flow cytometry, wound scratch, and transwell assays) and in vivo (nude mouse xenograft model). The interaction between SNHG22 and miR-128-3p, and the target genes of miR-128-3p were explored by online tools, qRT-PCR, western blot, and dual-luciferase reporter assay. Results: SNHG22 expression was gradually upregulated in ANTs, adenoma, and TTs. High expression levels of SNHG22 were significantly related to advanced clinicopathological factors and worse survival in patients with CRC. SNHG22 knockdown markedly prohibited CRC cell proliferation, migration, and invasion; and drove cell apoptosis in vitro; and hindered tumor growth in vivo. Mechanistic investigation showed that SNHG22 could bind to microRNA-128-3p (miR-128-3p) and attenuate its inhibitory effects on the expression levels and activity of E2F3. Rescue experiments exhibited that miR-128-3p inhibition or E2F3 upregulation can offset the functions of SNHG22 knockdown in CRC cells. Conclusion: Our findings support the existence of an interactive regulatory network of SNHG22, miR-128-3p, and E2F3 in CRC cell lines, indicating that the SNHG22/miR-128-3p/E2F3 axis is a novel diagnostic and therapeutic target in CRC.

MicroRNA-544 down-regulates both Bcl6 and Stat3 to inhibit tumor growth of human triple negative breast cancer

2016 ◽  
Vol 397 (10) ◽  
pp. 1087-1095 ◽  
Author(s):  
Zhengzhi Zhu ◽  
Shengying Wang ◽  
Jinhai Zhu ◽  
Qifeng Yang ◽  
Huiming Dong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Migration And Invasion ◽  
Specific Gene ◽  
Potential Biomarker ◽  
Mouse Xenograft Model

Abstract Triple negative breast cancer lacking estrogen receptor (ER), progesterone receptor and Her2 account for account for the majority of the breast cancer deaths, due to the lack of specific gene targeted therapy. Our current study aimed to investigate the role of miR-544 in triple negative breast cancer. Endogenous levels of miR-544 were significantly lower in breast cancer cell lines than in human breast non-tumorigenic and mammary epithelial cell lines. We found that miR-544 directly targeted the 3′-untranslated region (UTR) on both Bcl6 and Stat3 mRNAs, and overexpression of miR-544 in triple negative breast cancer cells significantly down-regulated expressions of Bcl6 and Stat3, which in turn severely inhibited cancer cell proliferation, migration and invasion in vitro. Employing a mouse xenograft model to examine the in vivo function of miR-544, we found that expression of miR-544 significantly repressed the growth of xenograft tumors. Our current study reported miR-544 as a tumor-suppressor microRNA particularly in triple negative breast cancer. Our data supported the role of miR-544 as a potential biomarker in developing gene targeted therapies in the clinical treatment of triple negative breast cancer.

Effect of MiR-32 on gastric carcinoma tumorigenesis by targeting Kruppel-like factor 4.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 76-76
Author(s):  
Chao Yan ◽  
Jianchun Yu ◽  
Weiming Kang
Keyword(s):  
Gastric Carcinoma ◽  
Cell Lines ◽  
Porous Membrane ◽  
Diagnostic Methods ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Comprehensive Treatment ◽  
Healthy Individuals ◽  
Gastric Carcinoma Cell ◽  
Tissue Samples

76 Background: Gastric cancer (GC) is a prevalent malignant cancer worldwide and is highly lethal because of its fast growth. Currently, the comprehensive treatment is the combination of surgery, chemotherapy and radiotherapy, which has made progress in the treatment of advanced GC. However, the accuracy of current diagnostic methods is not very satisfactory. To address these limitations and improve the survival rate and reduce mortality it is necessary to identify sensitive early diagnostic markers. MiR-32 has been reported as an oncogenic microRNA in many cancers, but its role in GC is unclear. Methods: We detected miR-32 expression in clinical gastric carcinoma tissue samples and adjacent normal tissue samples from the same patient. The expression of miR-32 was also detected in 40 gastric carcinoma patients’ plasma, as compared with the plasma of 40 healthy individuals. The proliferation ability of cells was monitored by the xCELLigence Real-Time Cell Analyzer (RTCA)-MP system. Transwell insert chambers with an 8 μm diameter porous membrane (Neuro Probe, MD, USA) were used for the migration/invasion assays. Also, the plasmid construction and luciferase reporter assay, western blotting analysis and immunofluorescence cell staining were performed. Data were analyzed with SPSS v.17.0 software. Results: We detected the expression level of miR-32 in two normal gastric tissue, the GES-1 cell line, and eight gastric carcinoma cell lines. The expression of miR-32 was significantly higher in tumor tissues as compared with normal tissues, p = 0.0016. The expression of miR-32 was significantly higher in 40 gastric carcinoma patients’ plasma, as compared with the plasma of 40 healthy individuals, p = 0.004.MiR-32 promotes the proliferation, migration and invasion of GC cells. The expression of KLF4 is negatively regulated by miR-32. Knockdown of KLF4 promotes cell proliferation, migration and invasion in GC cell-lines. Conclusions: In addition to identifying upregulated miR-32 as a diagnosis biomarker in clinical GC tissue and plasma, we have defined the biological functions of miR-32 as an oncogene in GC cells and explored the molecular mechanism of miR-32 in GC cells’ aggressive phenotype.

scholarly journals Circular RNA cir-ITCH Is a Potential Therapeutic Target for the Treatment of Castration-Resistant Prostate Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Shoubin Li ◽  
Chunhong Yu ◽  
Yunxia Zhang ◽  
Junjiang Liu ◽  
Yi Jia ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cell Lines ◽  
Therapeutic Target ◽  
Critical Role ◽  
Circular Rna ◽  
Migration And Invasion ◽  
Castration Resistant Prostate Cancer ◽  
Normal Prostate ◽  
Castration Resistant

cir-ITCH, a well-known tumor-suppressive circular RNA, plays a critical role in different cancers. However, its expression and functional role in prostate cancer (PCa) are unclear. Herein, we explored the potential mechanism and tumor-inhibiting role of cir-ITCH in PCa. Using reverse transcriptase polymerase chain reaction assay, we analyzed the expression of cir-ITCH in PCa and paired adjacent nontumor tissue samples resected during surgical operation, as well as in two cell lines of human PCa (LNCaP and PC-3) and the immortalized normal prostate epithelial cell line (RWPE-1). Cell viability and migration of PCa cell lines were evaluated using CCK-8 and wound-healing assays. Expression of key proteins of the Wnt/β-catenin and PI3K/AKT/mTOR pathways was detected using western blotting. We found that cir-ITCH expression was typically downregulated in the tissues and cell lines of PCa compared to that in the peritumoral tissue and in RWPE-1 cells, respectively. The results showed that cir-ITCH overexpression significantly inhibits the proliferation, migration, and invasion of human PCa cells and that reciprocal inhibition of expression occurred between cir-ITCH and miR-17. Proteins in the Wnt/β-catenin and PI3K/AKT/mTOR pathways were downregulated by overexpression of cir-ITCH both in androgen receptor-positive LNCaP cells and androgen receptor-negative PC-3 cells. Taken together, these data demonstrated that cir-ITCH plays a tumor-suppressive role in human PCa cells, partly through the Wnt/β-catenin and PI3K/AKT/mTOR pathways. Thus, cir-ITCH may serve as a novel therapeutic target for the treatment of PCa, especially castration-resistant prostate cancer.

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